Faculty Bibliography

Introduction: Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS^G12C. The phase 1/2 CodeBreaK 100 trial evaluated sotorasib in patients with pretreated advanced non-small cell lung cancer (NSCLC) harboring KRAS p.G12C. In the registrational phase 2 part, sotorasib showed an objective response rate (ORR) of 37.1% and a median progression-free survival (PFS) of 6.8 months. Here, we report on the activity of sotorasib in patients with treated brain metastases (BM).
Method(s): Patients from the phase 1/2 CodeBreaK 100 trial receiving 960mg dose were included. Patients with active untreated BM were excluded. Patients who had BM resected or had received radiation therapy ending >=4 weeks prior to the trial were eligible. Systemic response was assessed by independent central review per RECIST 1.1. The presence of neurologically stable/asymptomatic BM at baseline was determined by investigators. CNS response was retrospectively evaluated by central neuroradiologic review, using the response assessment in neuro-oncology BM (RANO-BM) criteria, in patients with >=1 target CNS lesions (>= 10mm) and/or non-target CNS lesions. For non-target lesions, stable disease (SD) refers to response that is neither complete response (CR) nor progressive disease (PD).
Result(s): 174 patients were included: 40 had stable BM (23.0%) while 134 (77.0%) had no BM at baseline. In the BM group, 65% had received prior radiotherapy, and 20% had received prior brain surgery. Systemic efficacy of sotorasib per RECIST 1.1 is shown in the Table. Per central RANO-BM review, 16 patients had baseline and >=1 on-treatment evaluable scans: 3 had target and 13 had non-target CNS lesions. 9 patients had 1 lesion, 2 had 4 lesions, and 5 had >=5 lesions. Of 13 patients with non-target CNS lesions, 2 had CR, 11 had SD. Of 3 patients with target lesions, 1 had SD, and 2 had PD. Overall, intracranial disease control was achieved in 14 of 16 patients (87.5%) with evaluable BM. Safety in the BM group was consistent with previous reports. [Formula presented]
Conclusion(s): Sotorasib demonstrated systemic durable anticancer activity, with a median PFS and OS of 5.3 and 8.3 months in NSCLC patients with stable BM previously treated with radiation or surgery. Intracranial complete responses were observed, with continued intracranial stabilization observed in the majority of patients with evaluable BM. Additional studies are ongoing to evaluate sotorasib in patients with active untreated BM (NCT04185883). Keywords: brain metastases, KRAS p.G12C, sotorasib (AMG 510)
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BACKGROUND:Immune checkpoint inhibitors (ICIs) can cause life-threatening cardiovascular adverse events (CVAEs) that may not be attributed to therapy. The outcomes of clinical trials may underestimate treatment-related adverse events due to restrictive eligibility, limited sample size, and failure to anticipate selected toxicities. We evaluated the incidence and clinical determinants of CVAEs in real-world population on ICI therapy. PATIENTS AND METHODS:Among 2 687 301 patients diagnosed with cancer from 2011 to 2018, 16 574 received ICIs for any cancer. Patients in the ICI and non-ICI cohorts were matched in a 1 : 1 ratio according to age, sex, National Cancer Institute comorbidity score, and primary cancer. The non-ICI cohort was stratified into patients who received chemotherapy (N = 2875) or targeted agents (N = 4611). All CVAEs, non-cardiac immune-related adverse events occurring after treatment initiation, baseline comorbidities, and treatment details were identified and analyzed using diagnosis and billing codes. RESULTS:Median age was 61 and 65 years in the ICI and non-ICI cohorts, respectively (P < 0.001). ICI patients were predominantly male (P < 0.001). Lung cancer (43.1%), melanoma (30.4%), and renal cell carcinoma (9.9%) were the most common cancer types. CVAE diagnoses in our dataset by incidence proportion (ICI cohort) were stroke (4.6%), heart failure (3.5%), atrial fibrillation (2.1%), conduction disorders (1.5%), myocardial infarction (0.9%), myocarditis (0.05%), vasculitis (0.05%), and pericarditis (0.2%). Anti-cytotoxic T-lymphocyte-associated protein 4 increased the risk of heart failure [versus anti-programmed cell death protein 1; hazard ratio (HR), 1.9; 95% confidence interval (CI) 1.27-2.84] and stroke (HR, 1.7; 95% CI 1.3-2.22). Pneumonitis was associated with heart failure (HR, 2.61; 95% CI 1.23-5.52) and encephalitis with conduction disorders (HR, 4.35; 95% CI 1.6-11.87) in patients on ICIs. Advanced age, primary cancer, nephritis, and anti-cytotoxic T-lymphocyte-associated protein 4 therapy were commonly associated with CVAEs in the adjusted Cox proportional hazards model. CONCLUSIONS:Our findings underscore the importance of risk stratification and cardiovascular monitoring for patients on ICI therapy.

BACKGROUND:We developed and validated a prognostic and predictive computational pathology risk score (CoRiS) using H&E stained tissue images from patients with early-stage non-small cell lung cancer (ES-NSCLC). METHODS:which comprised surgery + chemotherapy were used to validate CoRiS as predictive of added benefit to adjuvant chemotherapy (ACT) by comparing survival between different CoRiS defined risk groups. FINDINGS/RESULTS:(HR = 0.46, adj. P = .08). INTERPRETATION/CONCLUSIONS:CoRiS is a tissue non-destructive, quantitative and low-cost tool that could potentially help guide management of ES-NSCLC patients.

BACKGROUND:p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS:p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS:. CONCLUSIONS:p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

The aim of this study is to evaluate whether NIS radiomics can distinguish lung adenocarcinomas from granulomas on non-contrast CT scans, and also to improve the performance of Lung-RADS by reclassifying benign nodules that were initially assessed as suspicious. The screening or standard diagnostic non-contrast CT scans of 362 patients was divided into training (S_t, N = 145), validation (S_v, N = 145), and independent validation (S_iv, N = 62) sets from different institutions. Nodules were identified and manually segmented on CT images by a radiologist. A series of 264 features relating to the edge sharpness transition from the inside to the outside of the nodule were extracted. The top 10 features were used to train a linear discriminant analysis (LDA) machine learning classifier on St. In conjunction with the LDA classifier, NIS radiomics classified nodules with an AUC of 0.82 ± 0.04, 0.77, and 0.71 respectively on S_t, S_v, and S_iv. We evaluated the ability of the NIS classifier to determine the proportion of the patients in S_v that were identified initially as suspicious by Lung-RADS but were reclassified as benign by applying the NIS scores. The NIS classifier was able to correctly reclassify 46% of those lesions that were actually benign but deemed suspicious by Lung-RADS alone on S_v.

Evidence from real-world clinical settings is lacking with regard to first-line immunotherapy plus chemotherapy for the treatment of non-small cell lung cancer (NSCLC). Our aim was to describe outcomes for patients treated with first-line pembrolizumab-combination therapy for metastatic nonsquamous NSCLC in US oncology practices. Using an anonymized, nationwide electronic health record-derived database, we identified patients who initiated pembrolizumab plus pemetrexed-carboplatin in the first-line setting (May 2017 to August 2018) after diagnosis of metastatic nonsquamous NSCLC that tested negative for EGFR and ALK genomic aberrations. Eligible patients had ECOG performance status of 0-1. An enhanced manual chart review was used to collect outcome information. Time-to-event analyses were performed using the Kaplan-Meier method. Of 283 eligible patients, 168 (59%) were male; median age was 66 years (range 33-84); and the proportions of patients with PD-L1 tumor proportion score (TPS) of ≥ 50%, 1-49%, < 1%, and unknown were 28%, 27%, 28%, and 17%, respectively. At data cutoff on August 31, 2019, median patient follow-up was 20.3 months (range 12-28 months), and median real-world times on treatment (rwToT) with pembrolizumab and pemetrexed were 5.6 (95% CI 4.5-6.4) and 2.8 months (95% CI 2.2-3.5), respectively. Median overall survival (OS) was 16.5 months (95% CI 13.2-20.6); estimated 12-month survival was 59.5% (95% CI 53.3-65.0); rwProgression-free survival was 6.4 months (95% CI 5.4-7.8); and rwTumor response rate (complete or partial response) was 56.5% (95% CI 50.5-62.4). Median OS was 20.6, 16.3, 13.2, and 13.7 months for patient cohorts with PD-L1 TPS ≥ 50%, 1-49%, < 1%, and unknown, respectively. These findings demonstrate the effectiveness of pembrolizumab plus pemetrexed-carboplatin by describing clinical outcomes among patients with metastatic nonsquamous NSCLC who were treated at US oncology practices.

BACKGROUND:Previous studies have indicated Coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate. METHODS:We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariate logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes. RESULTS:We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the UK and Europe, followed by the USA and Canada (35.7%) and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (odds ratio [OR] = 3.57; 95% CI = 1.80 to 7.06), male (OR = 2.10; 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00; 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariate analysis, only age greater than 65 years (OR = 3.16; 95% CI = 1.45 to 6.88) and being male (OR = 2.29; 95% CI = 1.07 to 4.87) were associated with increased risk of severe events. CONCLUSION/CONCLUSIONS:Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate when compared with that of COVID-19 patients without cancer. Age and gender appear to be risk factors associated with a poorer prognosis.

Background: Time on treatment, also called time to treatmentdiscontinuation, is a readily available real-world effectiveness endpointhighly correlated at the patient-level with progression-free survival andmoderately to highly correlated with overall survival in clinical trials andreal-world data. In October 2016, pembrolizumab received FDA approvalbased on results from KEYNOTE-024, as a first-line monotherapy forpatients with metastatic NSCLCwith PD-L1 tumor proportion score (TPS)>=50%andnoEGFR/ALKgenomicaberrations, administereduntil diseaseprogression, unacceptable toxicity, or up to 24 months. In KEYNOTE-024,25%(39/154) of patients received 35 cycles (2 years) of pembrolizumabas initially assigned therapy. Our objective was to describe rwToT withfirst-line pembrolizumab in real-world oncology practice.
Method(s): Using the US nationwide Flatiron Health electronic healthrecord-derived, de-identified database, we included adult patients withpathologically confirmed advanced, PD-L1 TPS >=50% NSCLC whoinitiated first-line pembrolizumab monotherapy from November 2016-September 2019, with follow-up through September 2020. Eligibilitycriteria included ECOG performance status 0-2, PD-L1 TPS >=50%, noEGFR/ALK genomic aberration, and no known ROS1 aberration. Patientsenrolled in a clinical trial were excluded. Median rwToT and landmarkon-treatment rates were estimated using Kaplan-Meier method.
Result(s):(Table Presented)
Conclusion(s): Patients with key trial-eligible characteristics (ECOG 0-1,PD-L1 TPS >=50%, EGFR/ALK negative) experienced rwToT with firstlinepembrolizumab similar to the phase III pivotal clinical trial.Approximately 23% received at least 2 years of treatment, suggestinglong-term benefit of pembrolizumab monotherapy for PD-L1 TPS >=50%advanced NSCLC in a real-world setting.
Copyright International Association for the Study of Lung Cancer. Published by Elsevier Inc

OBJECTIVE:To identify stable and discriminating radiomic features on non-contrast CT scans to develop more generalisable radiomic classifiers for distinguishing granulomas from adenocarcinomas. METHODS:). To mitigate the variation of CT acquisition parameters, we defined 'stable' radiomic features as those for which the feature expression remains relatively unchanged between different sites, as assessed using a Wilcoxon rank-sum test. These stable features were used to develop more generalisable radiomic classifiers that were more resilient to variations in lung CT scans. Features were ranked based on two criteria, firstly based on discriminability (i.e. maximising AUC) alone and subsequently based on maximising both feature stability and discriminability. Different machine-learning classifiers (Linear discriminant analysis, Quadratic discriminant analysis, Support vector machines and random forest) were trained with features selected using the two different criteria and then compared on the two independent test sets for distinguishing granulomas from adenocarcinomas, in terms of area under the receiver operating characteristic curve. RESULTS:[n = 62]: maximum AUCs of 0.87 versus. 0.79; p-value = 0.021). These differences held for features extracted from scans with <3 mm slice thickness (AUC = 0.88 versus. 0.80; p-value = 0.039, n = 100) and for the ≥3 mm cases (AUC = 0.81 versus. 0.76; p-value = 0.034, n = 105). In both experiments, shape and peritumoural texture features had a higher stability compared with intratumoural texture features. CONCLUSIONS:Our study suggests that explicitly accounting for both stability and discriminability results in more generalisable radiomic classifiers to distinguish adenocarcinomas from granulomas on non-contrast CT scans. Our results also showed that peritumoural texture and shape features were less affected by the scanner parameters compared with intratumoural texture features; however, they were also less discriminating compared with intratumoural features.